Abstract 3631: A novel combination of Hedgehog inhibitors with carboplatin exhibits synergy in ovarian cancer treatment by altered regulation of DNA repair networks

Abstract

Ovarian cancer (OVCA) is the deadliest of all the reproductive cancers, affecting over 22,000 lives of women annually in the USA alone. In spite of their initial promising response rates to platinum drugs, more than 70% of patients relapse and die with the advanced disease. An important factor contributing to the poor outcomes in OVCA is platinum resistance (PR) and disease recurrence. Therefore, it is vital to understand the molecular mechanisms contributing to tumor resistance to platinum drugs and disease recurrence. Our preliminary studies identified aberrant activation of Hedgehog (Hh) signaling in advanced stage tumors and in OVCA cells, particularly those that are resistant to platinum agents. Further genetic and biochemical studies revealed altered expression of several cell cycle checkpoint and DNA repair genes involved in repair of platinum drug-induced DNA damage in these tumors and cell lines. Aberrant Hh signaling is implicated in the regulation of several signaling pathways including cell cycle, differentiation and DNA repair networks. Hence, we hypothesized that inhibition of Hh signaling could affect the expression of altered DNA damage response and repair networks and sensitize OVCA cells to platinum therapy. To this end, we evaluated two small molecule inhibitors of Hh signaling that target SMO (BMS-833923) and GLI transcription factors (GANT61) either alone or in combination with carboplatin in several OVCA cell lines by clonogenic and MTS cell survival assays. The therapeutic efficacy was assessed by calculating combination index (CI) values using CalcuSyn software. Simultaneously, we have also assessed the status of Hh signaling and several DNA damage response and repair networks that respond to platinum drugs. Interestingly, both the inhibitors of Hh signaling attenuated OVCA cells’ growth and their ability to form colonies. Consistent with this, inhibition of Hh signaling alone induced replication stress associated DNA damage responses (as evidenced by γH2AX foci) and compromised ATR-mediated cell cycle checkpoint responses. Similarly, combination treatment of Hh inhibitor (either SMO inhibitor or GLI inhibitor) with carboplatin potentiated the DNA damage induced by carboplatin and its cytotoxic effects in several ovarian cancer cell lines. Additionally, evaluation of combination treatments efficacies was confirmed in isogenic platinum sensitive (A2780) and resistant (A2780/CP70) OVCA cell lines. Moreover, analysis of combination therapeutic indexes revealed synergistic effects by demonstrating the CI values in the range of 0.3 to 0.49 (synergy defined as CI <1) at multiple dosage combinations. Collectively, our studies suggest the combination of Hh signaling inhibitors with carboplatin could be an effective therapeutic modality in synergistic killing of ovarian cancer cells and overcoming platinum resistance.

Citation Format: Sebastian M. Spencer, Kaushlendra Tripathi, Erhong Meng, Jennifer Scalici, Rodney P. Rocconi, Komaraiah Palle. A novel combination of Hedgehog inhibitors with carboplatin exhibits synergy in ovarian cancer treatment by altered regulation of DNA repair networks. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3631. doi:10.1158/1538-7445.AM2015-3631